Parkinson?s disease (PD) is a progressive neurodegenerative disorder symptomatically characterized by motor dysfunctions caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, many years prior to the onset of clinical motor symptoms, non-motor symptoms (NMS) such as cognitive deficits in executive processes that control goal-directed behavior, cognitive flexibility, and attention can be present. The causes of non-motor symptoms are not known, and while current PD treatments address dopamine deficiencies and motor symptoms, treatment with levodopa, the most common therapy for alleviating motor symptoms, has been shown to exacerbate cognitive impairments. The most common PD- linked mutation is the G2019S mutation in leucine-rich repeat kinase 2 (LRRK2), which causes autosomal- dominant PD with substantial similarity to idiopathic PD in terms of disease progression, suggesting common disease mechanisms. LRRK2 expression in the striatum peaks during early postnatal life coincident with the establishment of corticostriatal circuitry. Previous work in the lab has shown that G2019S-LRRK2 alters structural and functional development of corticostriatal circuits and abolishes corticostriatal LTP. This suggests that mutant LRRK2 may derail circuit development during a critical period when corticostriatal connectivity is highly sensitive to changes in network activity. This in turn suggests that such abnormal activity and loss of bidirectional plasticity could permanently affect striatal circuit function and behaviors such circuits support. Accordingly, I hypothesize that aberrant striatal synaptic plasticity and activity during development would impair cognitive functions mediated by corticostriatal circuitry. This proposal addresses the hypothesis by comparing the performance of G2019S-LRRK2 knockin and wild type young adult mice on executive tasks shown to be impaired in early-stage PD such as goal-directed learning, cognitive flexibility, and attention using a Bussey- Saksida mouse touchscreen system. Additionally, I will test whether early, in vivo intervention with a selective LRRK2 kinase inhibitor, MLi-2, can normalize the transient aberrant synaptic activity, thus preventing behavioral deficits later in life.
Parkinson's disease (PD), a neurodegenerative disorder affecting 2-3% of the world's population above age 65, manifests in its early stages with non-motor symptoms, including cognitive deficits. This proposal aims to characterize PD-linked impairments in executive functioning and to test reversibility in cognitive deficits by early postnatal interventions, aiding in the development of appropriate therapies. The study will use mouse models expressing the G2019S mutation in leucine-rich repeat kinase 2 (LRRK2), which carries a significant genetic risk for familial PD but whose effects on circuit function are not well understood.
